Recent advances in drug design and delivery have led to the development of an increasing number of highly lipophilic drug molecules which may be substrates for intestinal lymphatic transport. However, these drugs exhibit poor oral bioavailability owing either to low dissolution, P-glycoprotein efflux or CYP3A4 metabolism prior to absorption in the gastrointestinal tract, thus limiting their availability.
The adequate pharmaceutical formulation of such drugs remains a challenge which is not yet fully solved. It is well known that lipids are capable of enhancing lymphatic transport of hydrophobic drugs, thereby reducing drug clearance resulting from hepatic first-pass metabolism. This improves drug absorption, bioavailability profiles, activity and lowers toxicity. The commercial success of self-emulsifying drug delivery system (SEDDS) formulations such as Neoral® (cyclosporin A), Norvir® (ritonavir) and Fortovase® (saquinavir) has raised the interest in such promising emulsion-based delivery systems to improve the oral bioavailability of lipophilic drugs (1). It is believed that SEDDS which spread out as fine oil droplets in the GI tract enhance the bioavailability by promoting lymphatic transport of the lipophilic drugs. Indeed, it was recently proved that the extent of lymphatic transport via the thoracic duct was 27.4% of the halofantrine dose for the animals dosed with the structured triglyceride SMEDDS (1). In addition, it was recently reported that under certain circumstances, the lymphatics may provide the primary route of drug absorption and lead to drug concentration in the lymph some 5-10,000 times higher than in systemic plasma (2). Recent advances in drug design and delivery, have also led to the development of an increasing number of highly lipophilic drug molecules which may be substrates for intestinal lymphatic transport. There is an increase in interest in the role of the lymphatic in determining drug absorption and bioavailability profiles, activity and toxicity. For example, an increasing body of evidence has shown that certain lipids are capable of inhibiting both presystemic drug metabolism and p-glycoprotein-mediated (Pgp-mediated) drug efflux by the gut wall (3)
EP 480,729 (4) discloses a microencapsulation method for oral administration of a drug dispersed in an oil droplet. The oil droplet is encapsulated using a polysaccharide which has metal-chelating capacity and a water-soluble polymer. The encapsulation protects the drug from release in the stomach, while providing rapid release in the small intestine. Since the drug in the oil droplet is preferentially absorbed by lymphatic absorption, it is protected from degradation by hepatic first-pass metabolism.
U.S. Pat. No. 5,965,160 (5) discloses a self-emulsifying oily formulation (SEOF) which may contain a hydrophobic drug, comprising an oil component and a surfactant. The SEOF is characterized in that the oil component comprises an oily carrier and a cationic lipid and, optionally, a lipophilic oily fatty alcohol. The oil-in-water emulsion which forms upon mixture of the SEOF with an aqueous solution has oily droplets which are positively charged.
Cook, R. O., et al. (6) describes a process for generating sustained release particles for pulmonary drug delivery. According to this process nanoparticles of the hydrophilic, ionised drug terbutaline sulphate are entrapped within hydrophobic microspheres using a spray-drying approach.
Khoo, S M, et al. (7) disclose dispersed lipid-based formulations for the oral delivery of lipophilic drugs such as Halofantrine. Both a lipidic self-emulsifying drug delivery system (SEDDS) and a self-microemulsifying drug delivery system (SMEDDS) are described. The systems comprise a triglyceride, mon-/diglyceride, nonionic surfactant, a hydrophilic phase and the drug substance. Optimised formulations were medium-chain triglyceride (MCT) SEEDS and SMEDDS, and a long-chain triglyceride (LCT) SMEDDS.
Holm, R, et al. (1) describe a SMEDDS containing triglycerides with different combinations of medium-chain and long-chain fatty acids, where the different fatty acids on the glycerol backbone exhibit different metabolic fates.
Christensen, K. L., et al. (9) describe the preparation of stable dry emulsions which are able to reform the original o/w emulsion by reconstitution in water. The dry emulsions contained a water-soluble polymer such as hydroxypropylmethylcellulose (HPMC), methylcellulose or povidone, as solid carrier, and fractionated coconut oil. The liquid o/w emulsions were spray dried in a laboratory spray drier. The droplet size of the reconstituted emulsion was approximately 1 μm. Tacrolimus (Prograf®) is a macrolide immunosuppressive agent (MW of 804) that is derived from the fungus Streptomyces tsukubaensis, and has been shown to be effective in graft rejection prophylaxis and in the management of acute and steroid- or cyclosporine-resistant transplant rejection. tacrolimus is considered as an alternative to cyclosporine immunosuppression and was shown to be 10-100 times more potent than cyclosporine. tacrolimus was approved by the FDA for the prevention of liver transplant rejection in April, 1994.
Like cyclosporine, pharmacokinetic parameters of tacrolimus show high inter- and intra-individual variability and both drugs have a narrow therapeutics index, necessitating therapeutics whole-blood drug monitoring to optimize treatment. Absorption and oral bioavailability (10-25%) of tacrolimus are poor, with reduced rate and extent of absorption in the presence of food. Tacrolimus is rapidly, albeit incompletely, absorbed in the gastrointestinal tract. Tacrolimus peak concentration whole blood (Cmax) is attained approximately 1-2 hours after oral administration. Due to the low aqueous solubility, tissue distribution of tacrolimus following oral or parenteral therapy is extensive (10). Tacrolimus is mainly bound to albumin and alpha1-acid glycoprotein. Erythrocytes bind 75-80% of the drug resulting in whole blood concentrations that are 10- to 30 times higher than plasma concentrations (10). Tacrolimus is almost completely metabolized prior to elimination. Metabolism is via cytochrome P450 (CYP) 3A4 isoenzymes in the liver and, to a lesser extent, CYP3A4 isoenzymes and P-glycoprotein in the intestinal mucosa. The elimination half-life of tacrolimus in liver transplant patients is about 12 hours. Less than 1% of the dose is excreted unchanged in the urine. The P-glycoprotein efflux of tacrolimus from intestinal cells back into the gut lumen allows for CYP3A4 metabolism prior to absorption, thus limiting tacrolimus availability (11). When tacrolimus is administered with inhibitors of both CYP3A4 and P-glycoprotein (e.g., diltiazem, erythromycin, or ketoconazole), oral bioavailability enhancement is observed. There is a need for oral bioavailability enhancement of tacrolimus by drug delivery.
Uno, T, et al. (12) describe an oil-in-water (o/w) emulsion of the drug tacrolimus based on oleic acid. The mean diameters of the o/w emulsion droplets were 0.47 μm. The disclosed formulation exhibited bioavailability, pharmacokinetic advantages and potential usefulness of the emulsion as a carrier for tacrolimus enteral route compared to standard marketed formulation.
U.S. Pat. No. 6,884,433 (13) describe sustained release formulation containing tacrolimus as well as other macrolide compounds. The sustained release formulation disclosed therein comprises a solid dispersion of tacrolimus or its hydrates, in a mixture comprising a water soluble polymer (such as hydroxypropylmethylcellulose) and a water insoluble polymer (such as ethylcellulose) and an excipient (such as lactose). In the dispersion, the particle size is equal to or less than 250 μm.
In order to overcome first pass metabolism and thus low oral bioavailability intestinal lymphatic transport of drugs can be therefore, exploited. As previously mentioned, highly lipophilic compounds reach systemic circulation via the lymphatics. The majority of fatty acids, with chain lengths of 14 and above, were found to be recovered in thoracic lymph (14).
In addition, the size is one of the most important determinants of lymphatic uptake. Optimum size for lymphatic uptake was found to be between 10 and 100 nm (15). However, uptake is more selective and slower as the particle size increases. Larger particles may be retained for longer periods in the Peyer's patches, while smaller particles are transported to the thoracic duct (16). Oral administration of polymeric nano- and microparticles are taken up by lymphatic system through M cells of Peyer's patches of intestine was evidenced and proved in the literature (17). Nanoparticles coated with hydrophobic polymers tend to be easily captured by lymphatic cells in the body (18).
Another method for encapsulation of drugs into microparticles was described by Bassett et al. (19). The method involves phase inversion by dissolving the drug and a first polymer in a solvent and adding to the thus formed mixture a second polymer dissolved in a “non-solvent” which leads to the spontaneous formation of polymer coated micro or nanoparticles.